Process for producing tricyclic fused heterocyclic derivative

ABSTRACT

A process for easily and industrially advantageously producing both a tricyclic fused heterocyclic derivative having acetylcholinesterase inhibitory activity and an intermediate for the derivative. The process for producing the target compounds comprises the following reaction.

This application is a U.S. national stage of International ApplicationNo. PCT/JP 01/08165 filed Sep. 20. 2001.

TECHNICAL FIELD

The present invention relates to a process for producing a tricyclicfused heterocyclic derivative having acetylcholinesterase inhibitoryactivity which is useful as a medicament and an intermediate thereof.

BACKGROUND TECHNIQUE

Until now, as a process for synthesizing a tricyclic fused heterocyclicderivative having acetylcholinesterase inhibitory activity and anintermediate thereof, Friedel-Crafts reaction of a tricyclic fusedheterocyclic ring with an acid chloride in the presence of aluminiumchloride in a halogen solvent has been reported (JP 7-206854 A).

OBJECTS OF THE INVENTION

Since in the aforementioned previous process, 1,2-dichloroethane andmethylene chloride which are an environmental pollutant and areremarkably restricted in their use are used as a reaction solvent, andmany steps are involved, it is desired to develop a process forproducing a tricyclic fused heterocyclic derivative and an intermediatethereof, which is inexpensive and simple.

SUMMARY OF THE INVENTION

The present inventors studied various processes for producing atricyclic fused heterocyclic derivative and, as a result, found for thefirst time that when a tricyclic fused heterocyclic ring and apiperidinecarboxylic acid derivative are subjected todehydration-condensation in the presence of a polyphosphoric acid, thepiperidinecarboxylic acid derivative is bound to a particular desiredposition of the tricyclic fused heterocyclic ring, thereby obtaining thedesired derivative at a better yield and at the low cost and simply, andthat this process is a satisfactory industrial process. Based on thesefindings, the present inventors intensively studied and completed thepresent invention.

That is, the present invention relates to:

-   -   (1) A process for producing a compound represented by the        formula:        wherein the symbols are as defined hereinafter, or a salt        thereof, which comprises:    -   reacting a compound represented by the formula:        wherein one of the ring A and the ring B is an optionally        substituted heterocyclic ring, and the other is an optionally        substituted 5- to 8-membered ring which may contain hetero        atom(s), or a salt thereof, with a compound represented by the        formula:        wherein R is a hydrogen atom, an optionally substituted alkyl        group or an optionally substituted acyl group, and n is an        integer of 1 to 6, or a salt thereof, in the presence of a        phosphorus compound;    -   (2) The process according to the above (1), wherein the        phosphorus compound is polyphosphoric acid;    -   (3) The process according to the above (1), wherein the formula:        wherein each of the ring A″ and the ring B″ ring is an        optionally substituted nitrogen-containing heterocyclic ring;    -   (4) The process according to the above (1), wherein R is an        optionally substituted acyl group;    -   (5) The process according to the above (1), wherein R is an        acetyl group;    -   (6) A process for producing        8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,        which comprises reacting,        2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with        1-acetyl-4-piperidinepropionic acid in the presence of a        phosphorus compound;    -   (7) A process for producing a compound represented by the        formula:        wherein the symbols are as defined hereinafter, or a salt        thereof, which comprises:    -   reacting a compound represented by the formula:        wherein one of the ring A and the ring B is an optionally        substituted heterocyclic ring, and the other is an optionally        substituted 5- to 8-memberd ring which may contain hetero        atom(s), or a salt thereof, with a compound represented by the        formula:        wherein R′ is an optionally substituted acyl group, and n is an        integer of 1 to 6, in the presence of a phosphorus compound, and    -   deacylating the resulting compound represented by the formula:        wherein the symbols are as defined above, or a salt thereof;    -   (8) The process according to the above (7), wherein deacylation        is conducted with about 1 to about 6 N hydrochloric acid;    -   (9) A process for producing        8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,        which comprises reacting        1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with        1-acetyl-4-piperidinepropionic acid in the presence of a        phosphorus compound, and deacetylating the resulting        8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one;    -   (10) A process for producing a compound represented by the        formula:        wherein the symbols are as defined hereinafter, or a salt        thereof, which comprises:    -   reacting a compound represented by the formula:        wherein one of the ring A ring and the ring B is an optionally        substituted heterocyclic ring, and the other is an optionally        substituted 5- to 8-membered ring which may contain hetero        atom(s), or a salt thereof, with a compound represented by the        formula:        wherein R′ is an optionally substituted acyl group, and n is an        integer of 1 to 6, or a salt thereof, in the presence of a        phosphorus compound,    -   deacylating the resulting compound represented by the formula:        wherein the symbols are as defined, or a salt thereof, and    -   reacting the resulting compound represented by the formula:        wherein the symbols are as defined above, or a salt thereof,        with a compound represented by the formula:        wherein the ring C is an optionally substituted benzene ring,        and W is a leaving group, or a salt thereof;    -   (11) The process according to the above (10), wherein the ring C        is a benzene ring substituted with a halogen;    -   (12) A process for producing        8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,        which comprises reacting        1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with        1-acetyl-4-piperidinepropionic acid in the presence of a        phosphorus compound, deacetylating the resulting        8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,        and reacting the resulting        8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one        with 3-fluorobenzyl chloride; and the like.

DETAILED EXPLANATION OF THE INVENTION

As the “heterocyclic ring” in the “optionally substituted heterocyclicring” represented by the ring A or the ring B in the above formulas, forexample, a 5- to 9-membered ring containing 1 to 3 hetero atom(s)selected from a nitrogen atom, an oxygen atom and a sulfur atom is used.Specifically, for example, pyridine, pyrazine, pyrimidine, imidazole,furan, thiophene, pyrrolidine, piperidine, hexamethyleneimine,tetrahydrofuran, piperazine, morpholine, thiomorpholine, etc., are used.In particular, a 5- to 9-membered non-aromatic heterocyclic containingone hetero atom or the same or different two hetero atoms (e.g.pyrrolidine, piperidine, hexamethyleneimine, tetrahydrofuran,piperazine, morpholine, thiomorpholine, etc.) is preferable. Inparticular, for example, a non-aromatic heterocyclic ring containing onehetero atom selected from a nitrogen atom, an oxygen atom and a sulfuratom, and a non-aromatic heterocyclic ring containing one nitrogen atomand one hetero atom selected from a nitrogen atom, an oxygen atom and asulfur atom are frequently used.

As the “5- to 8-membered ring which may contain hetero atom(s)”represented by the ring A or the ring B, a 5- to 8-membered heterocyclicor carbocyclic ring is used, and the ring may be substituted. The 5- to8-membered carbocyclic ring may be a benzene ring, or a saturated orunsaturated ring and, for example, benzene, cyclopentane, cyclopentene,cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene,cycloheptadiene, etc., are used. In addition, when the ring A or thering B has hetero atom(s) in the ring, that is, the ring A or the ring Bis a heterocyclic ring, as the hetero atom(s), for example, 1 to 3atom(s) selected from a nitrogen atom, an oxygen atom and a sulfur atomis (are) used, and the ring A or the ring B may be either aromatic ornon-aromatic. As the aromatic heterocyclic ring, pyridine, furan,thiophene, etc., are used. As the non-aromatic heterocyclic ring, anon-aromatic heterocyclic ring exemplified with respect to the ring A orthe ring B is preferable.

That is, examples of the compound (I) include1H,3H-naphtho[1,8-cd][1,2]oxazine, naphtho[1,8-de]-1,3-oxazine,naphtho[1,8-de]-1,2-oxazine, 1,2,2a,3,4,5-hexahydrobenzo[cd]indole,2,3,3a,4,5,6-hexahydro-1H-benzo[de]quinoline,4H-pyrrolo[3,2,1-ij]quinoline,1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline,5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline, 1H,5H-benzo[ij]quinolizine,azepino[3,2,1-hi]indole, 1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole,1H-pyrido[3,2,1-jk][1]benzazepine,5,6,7,8-tetrahydro-1H-pyrido[3,2,1-jk][1]benzazepine,1,2,5,6,7,8-hexahydro-1H-pyrido[3,2,1-jk][1]benzazepine,2,3-dihydro-1H-benzo[de]isoquinoline,1,2,3,4,4a,5,6,7-octahydronaphtho[1,8-bc]azepine,2,3,5,6,7,8-hexahydro-1H-pyrido[3,2,1-jk][1]benzazepine, and the like.

As the compound (1), for example, a compound represented by the formula:

wherein R⁶ is a hydrogen atom, an optionally substituted hydrocarbongroup or an optionally substituted acyl group, and the other symbols areas defined above, or a salt thereof is preferable.

As the compound (I), a compound represented by the formula:

wherein the ring A′ is an optionally substituted 5- or 6-memberednitrogen-containing heterocyclic ring, and the ring B′ is an optionallysubstituted 5- to 7-membered nitrogen-containing heterocyclic ring, or asalt thereof, that is, a compound represented by the formula:

wherein the symbols are as defined above, or a salt thereof is morepreferable.

As the compound (I), a compound represented by the formula:

wherein each of the ring A″ and the ring B″ is an optionally substitutednitrogen-containing heterocyclic ring, or a salt thereof is mostpreferable.

The ring A and the ring B may be substituted, and the substituent may bepresent at any arbitrary carbon atom of the ring A and the ring B. Asthe substituent(s), for example, 1 to 5 substituent(s) selected from ahalogen atom (e.g. fluoro, chloro, bromo, iodo, etc.), a nitro group, acyano group, an oxo group, a hydroxy group, a C₁₋₄alkoxy group (e.g.methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.), a C₁₋₄alkylthio group (e.g. methylthio, ethylthio, propylthio, etc.), an aminogroup, a mono-or di-C₁₋₄ alkylamino group (e.g. methylamino, ethylamino,propylamino, dimethylamino, diethylamino, etc.), a 5- to 7-memberedcyclic amino group which may have 1 to 3 hetero atom(s), for example,selected from a nitrogen atom, an oxygen atom and a sulfur atom inaddition to carbon atoms and one nitrogen atom (e.g., pyrrolidino,piperidino, morpholino, thiomorpholino, etc.), a C₁₋₄alkyl-carbonylamino group (e.g. acetylamino, propionylamino,butyrylamino, etc.), a C₁₋₄ alkylsufonylamino group (e.g.methylsulfonylamino, ethylsulfonylamino, etc.), a C₁₋₄ alkoxy-carbonylgroup (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), acarboxyl group, a C₁₋₆ alkyl-carbonyl group (e.g. methylcarbonyl,ethylcarbonyl, propylcarbonyl, etc.), a carbamoyl group, a mono- ordi-C₁₋₄ alkyl-carbamoyl group (e.g. methylcarbamoyl, ethylcarbamoyl,etc.), a C₁₋₆ alkylsulfonyl group (e.g. methylsulfonyl, ethylsulfonyl,propylsulfonyl etc.), etc., are used.

Among them, an oxo group, and a C₁₋₆ alkyl group such as methyl arepreferable and, inter alia, an oxo group is preferable.

When the ring A and the ring B have a nitrogen atom in the ring, thoserings may have a substituent on the nitrogen atom. That is, the ring Aand the ring B may have>N—R⁶wherein R⁶ is a hydrogen atom, an optionally substituted hydrocarbongroup or an optionally substituted acyl group, in the ring.

As the “optionally substituted hydrocarbon group” represented by R⁶, forexample, a C₁₋₆ alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl,etc.) and a C₇₋₁₀ aralkyl group (e.g. phenylmethyl, phenylethyl, etc.),etc., which may be substituted with 1 to 3 substituent(s) selected froma halogen atom (e.g. fluoro, chloro, bromo, iodo, etc.), a nitro group,a C₁₋₄ alkoxy group (e.g. methoxy, ethoxy, etc.), a hydroxy group, etc.,are preferable. In particular, an unsubstituted benzyl group isfrequently used.

As the “optionally substituted acyl group” represented by R⁶, forexample, formyl, C₁₋₆ alkyl-carbonyl (e.g. acetyl, propionyl, etc.),benzoyl, C₁₋₆ alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl,etc.), benzenesulfonyl, C₁₋₆ alkoxy-carbonyl (e.g. methoxycarbonyl,ethoxycarbonyl, t-butoxycarbonyl, etc.), benzyloxycarbonyl, etc., whichmay be substituted with 1 to 3 substituent(s) selected from a halogenatom (e.g. fluoro, chloro, bromo, iodo, etc.), a nitro group, aC₁₋₆alkoxy group (e.g. methoxy, ethoxy, etc.), a hydroxy group, an aminogroup, a mono- or di-C₁₋₆ alkylamino group (e.g. methylamino,ethylamino, dimethylamino, diethylamino, etc.), etc., are preferable.

In the aforementioned formulas, examples of a substituent in the ringA′, the ring B′, the ring A″ and the ring B″ include the samesubstituents as those in the ring A and the ring B.

As the substituent of the ring A′ and the ring B′, an oxo group ispreferable, and the ring A″ and the ring B″ are preferablyunsubstituted.

In the aforementioned formulas, examples of the “optionally substitutedalkyl group” represented by R include a C₁₋₆ alkyl group (e.g. methyl,ethyl, n-propyl, isopropyl, etc.) optionally substituted with 1 to 3substituent(s) selected from (1) a halogen atom (e.g. fluoro, chloro,bromo, iodo, etc.), (2) nitro group, (3) a C₁₋₆alkoxy group (e.g.methoxy ethoxy, etc.), (4) a hydroxy group, (5) a phenyl groupoptionally substituted with 1 to 3 substituent(s) selected from C₁₋₆alkyl (e.g. methyl, ethyl, etc.), a halogen atom (e.g. fluoro, chloro,bromo, iodo, etc.), nitro, cyano, amino, mono- or di-C₁₋₆ alkylamino(e.g. methylamino, ethylamino, dimethylamino, diethylamino, etc.),hydroxy, C₁₋₆alkoxy (e.g. methoxy, ethoxy, etc.), phenyl-C₁₋₆ alkoxy(e.g. benzyloxy, etc.), C₁₋₄ alkylenedioxy (e.g. methylenedioxy, etc.),etc.

Examples of the “optionally substituted acyl group” represented by R andR′ include the same “optionally substituted acyl group” as thatrepresented by R⁶.

As R and R′, an optionally substituted acyl group is preferable, and aC₁₋₆ alkyl-carbonyl group (e.g. acetyl group) is more preferable.

In the aforementioned formulas, while n is an integer of 1 to 6, 2 or 3are preferable, and 2 is more preferable.

In the aforementioned formulas, examples of the “optionally substitutedbenzene ring” represented by the ring C include a benzene ringoptionally substituted with 1 to 3 substituent(s) selected from C₁₋₆alkyl (e.g. methyl, ethyl, etc.), halogen atom (e.g. fluoro, chloro,bromo, iodo, etc.), nitro, cyano, amino, mono-or di-C₁₋₆alkylamino (e.g.methylamino, ethylamino, dimethylamino, diethylamino, etc.), hydroxy,C₁₋₆ alkoxy (e.g. methoxy, ethoxy, etc.), phenyl-C₁₋₄ alkoxy (e.g.benzyloxy, etc.) and C₁₋₄ alkylenedioxy (e.g. methylenedioxy, etc.).

As the ring C, a benzene ring substituted with a halogen atom such asfluoro, etc., amino, etc., is preferable, and a benzene ring substitutedwith a halogen atom is more preferable.

Examples of the “leaving group” represented by W in the above formulasinclude a halogen atom (e.g. chloro, bromo, iodo, etc.), optionallyhalogenated C₁₋₆ alkylsulfonyloxy (e.g. methanesulfonyloxy,ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), optionallysubstituted C₆₋₁₀ arylsulfonyloxy, etc. Examples of the substituent ofthe “optionally substituted C₆₋₁₀ arylsulfonyloxy” include 1 to 3substituent(s) selected from a halogen atom, optionally halogenatedC₁₋₆alkyl and optionally halogenated C₁₋₆ halogenated alkoxy. Examplesof the “optionally substituted C₆₋₁₀arylsulfonyloxy” includebenzenesulfonyloxy, p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy,2-naphthalenesulfonyloxy, etc.

As W, a halogen atom such as chloro is preferable.

As a salt of the compounds represented by the formulas (I), (II), (II′),(III), (III′), (IV) and (V), for example, salts with inorganic acids(e.g. hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuricacid, nitric acid, etc.), or salts with organic acids (e.g. acetic acid,trifluoroacetic acid, formic acid, propionic acid, fumaric acid, maleicacid, succinic acid, tartaric acid, citric acid, malic acid, oxalicacid, benzoic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, etc.) are used. Further, when each compound hasan acidic group such as —COOH, the compound may form a salt withinorganic bases (e.g. alkali metal and alkaline earth metal such assodium, potassium, calcium and magnesium, etc., and ammonia) or organicbases (e.g. triethylamine, triethylamine, pyridine, picoline,ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,N,N-dibenzylethylenediamine, etc.).

A process for producing the compound (III), (IV) or (VI) which is usefulas a tricyclic fused heterocyclic derivative having acetylcholinesteraseinhibitory activity and an intermediate thereof will be described below.

In the process of the present invention, a compound (I) and a compound(II) are subjected to dehydration-condensation in the presence of aphosphorus compound to obtain a compound (III).

The amount of the compound (II) to be used is about 1 to 10 moles,preferable about 1 to 2 moles relative to 1 mole of the compound (I).

Examples of the phosphorus compound used in the present inventioninclude 1 or 2 or more selected from polyphosphoric acid, polyphosphoricacid ester, phosphorus pentaoxide, phosphorus pentaoxide-phosphoricacid, phosphorus pentaoxide-methanesulfonic acid, phosphorusoxychloride-zinc (II) chloride, etc. Among them, polyphosphoric acid ispreferable.

The amount of the phosphorus compound to be used is about 1 to 100moles, preferably about 1 to 20 moles relative to 1 mole of the compound(II).

The reaction temperature is usually about 0 to 160° C., preferable about20 to 120° C. The reaction time is usually about 0.1 to 30 hours,preferably about 1 to 10 hours.

In this reaction, it is preferable that the phosphorus compound is usedas it is as a solvent. The reaction may be carried out in the presenceof a solvent which is inert to the reaction. As the “inert solvent”,aromatic hydrocarbons (e.g. benzene, toluene, xylene, chlorobenzene,etc.), ethers (e.g. diglyme, diethyl ether, diisopropyl ether, t-butylmethyl ether, diphenyl ether, dioxane, 1,2-dimethoxyethane, etc.),aliphatic hydrocarbons (e.g. hexane, pentane, cyclohexane, etc.), amides(e.g. N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidone, hexamethylphosphorictriamide, etc.), nitrites(e.g. acetonitrile, propionitrile, etc.), and a mixture of 2 or morethereof may be used. Among them, toluene, tetrahydrofuran,N,N-dimethylformamide, etc., are preferable.

When the compound (I) and the compound (II) are commercially available,they may be used as they are, or those compounds may be prepared by amethod known per se (JP-A 7-206854) or a similar method.

Next, a compound wherein R is an optionally substituted acyl group inthe formula (III), that is, a compound (III′) may be further deacylatedto obtain a compound (IV).

In this reaction, a deacylating agent such as hydrochloric acid,hydrobromic acid, sulfuric acid and the like is usually used. Amongthem, hydrochloric acid is preferable, and the concentration ofhydrochloric acid is preferably about 1 to 12 N, more preferably about 1to 6 N.

The amount of the deacylating agent to be used is about 1 to 50 moles,preferably about 2 to 5 moles relative to 1 mole of the compound (IV).

The reaction temperature is usually about 20 to 120° C., preferablyabout 60 to 100° C. The reaction time is usually about 0.1 to 30 hours,preferably about 1 to 15 hours.

In this reaction, 1 to 12 N hydrochloric acid is used as it is as asolvent in some cases, but the reaction may also be carried out in thepresence of a solvent which is inert to the reaction. As the “inertsolvent”, aromatic hydrocarbons (e.g. benzene, toluene, xylene,chlorobenzene, etc.), ethers (e.g. diglyme, diethyl ether, diisopropylether, t-butyl methyl ether, diphenyl ether, dioxane,1,2-dimethoxyethane, etc.), aliphatic hydrocarbons (e.g. hexane,pentane, cyclohexane, etc.), alcohols (e.g. methanol, ethanol, isopropylalcohol, 2-butanol, t-butanol, 2-methyl-2-butanol, etc.), and a mixtureof 2 or more thereof may be used. Among them, toluene, tetrahydrofuranand ethanol are preferable.

Then, the thus obtained compound (IV) or a compound wherein R is ahydrogen atom in the formula (III) and a. compound (V) are reacted inthe presence or the absence of a base to obtain a compound (VI).

The amount of the compound (V) to be used is about 1 to 10 moles,preferably about 1 to 3 moles relative to 1 mole of the compound (IV).

Examples of the “base” include hydrides of an alkali metal or analkaline earth metal (e.g. lithium hydride, sodium hydride, potassiumhydride, calcium hydride, etc.), amides of an alkali metal or analkaline earth metal (e.g. lithium amide, sodium amide, lithiumdiisopropylamide, lithium dicyclohexylamide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide, etc.), lower alkoxides of an alkali metal or analkaline earth metal (e.g. sodium methoxide, sodium ethoxide, potassiumtert-butoxide, etc.), carbonates of an alkali metal or an alkaline earthmetal (e.g. sodium bicarbonate, sodium carbonate, potassium carbonate,etc.), organic bases (e.g. organic bases such as amines such astriethylamine, diisopropylethylamine, N-methylmorpholine,dimethylaminopyridine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN(1,5-diazadicyclo[4.3.0]non-5-ene), etc.; basic heterocyclic compoundssuch as pyridine, imidazole, and 2,6-lutidine, etc.), etc. Among them,carbonates of an alkali metal or an alkaline earth metal are preferable.The amount of the “base” to be used is about 1 to 10 moles, preferablyabout 1 to 3 moles relative to 1 mole of the compound (V).

The reaction temperature is usually about −10 to 150° C., preferablyabout 0 to 80° C. The reaction time is usually about 0.1 to 30 hours,preferably about 1 to 15 hours.

This reaction is carried out in the presence of a solvent which is inertto the reaction. As the “inert solvent”, for example, aromatichydrocarbons (e.g. benzene, toluene, xylene, chlorobenzene, etc.),ethers (e.g. diethyl ether, diisopropyl ether, t-butyl methyl ether,diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.),aliphatic hydrocarbons (e.g. hexane, pentane, cyclohexane, etc.), amides(e.g. N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidone, hexamethylphosphorictriamide, etc.), sulfoxides(e.g. dimethyl sulfoxide, etc.), primary alcohols (e.g. methanol,ethanol, etc.), nitrites (e.g. acetonitrile, propionitril, etc.), waterand a mixture of 2 or more thereof are used. Among them,N,N-dimethylformamide, ethanol, acetonitrile, etc., are preferable.

This reaction is carried out in the presence of an inorganic salt (e.g.halogenated alkali metal salt such as sodium iodide, sodium bromide,potassium iodide, potassium bromide, etc.) as necessary.

The thus obtained compound (III), (IV) or (VI) can be isolated andpurified from a reaction mixture by a separating means known per se(e.g. concentration, concentration under reduced pressure, solventextraction, precipitation, recrystallization, transferring dissolution,chromatography, etc.).

The desired end compounds [compound (III) (except that R is a hydrogenatom) and compound (VI)] have acetylcholinesterase inhibitory activity.Therefore, these compounds are useful as an agent for preventing ortreating senile dementia. Further, they can be used as a bladderexcretion modifier. For example, they can be used as an agent forpreventing or treating urination disorder caused by the following 1) to6), in particular, urination difficulty: 1) prostatomegary, 2) bladdercervical obstruction, 3) neurogenic bladder, 4) diabetes, 5) operationand 6) bladder muscle tension reduction. Further, they are also usefulas an agent for preventing or treating urination disorder such aspollakiuria, urinal incontinence and the like.

The following Examples illustrate the present invention in more detailbut do not limit the present invention.

Abbreviations used in the present text have the following meanings.

-   -   s: singlet    -   d: doublet    -   t: triplet    -   m: multiplet    -   J: coupling constant    -   Hz: Hertz    -   CDCl₃: heavy chloroform    -   DMSO-d₆: heavy dimethyl sulfoxide    -   ¹H-MMR: proton nuclear magnetic resonance

¹H-NMR spectrum is measured with Brukka DPX 300 (300 MHz) typespectrometer using tetramethylsilane as an internal standard, and thetotal δ value is shown in ppm.

EXAMPLE 1

Synthesis of8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one

A mixture of 2.5 kg of 1-acetyl-4-piperidinepropionic acid, 2.17 kg (1equivalent) of 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-oneand 26.0 kg of polyphosphoric acid was stirred at about 105° C. for 8hours under nitrogen and 13 L of cold water at about 5° C. was slowlyadded dropwise thereto while maintaining about 70° C. Further, 25 L of amixture of toluene-acetonitrile (1:1) was added at about 55° C. and pHwas adjusted to about 8.5 by adding 25% aqueous ammonia solution (about50 L) while maintaining about 55° C. The layers were separated, 10 L ofa mixture of toluene-acetonitrile (1:1) was added to the aqueous layer,and the layers were separated. The organic layers were combined andconcentrated to a volume of the solution of about 10 L. To the residuewas added 9 L of isopropyl ether at about 20° C. to precipitatecrystals. The mixture was stirred at about 20° C. for about 1.5 hoursand then at about 5° C. for about 1.5 hours. Precipitated crystals wereseparated, washed with about 6 L of a mixture of isopropyl ether-ethylacetate (1:1) cooled to about 5° C., and 10 L of isopropyl ether cooledto about 5° C., and dried to obtain 3.78 kg (yield 85%) of the desiredcompound as crystals.

Elementary Analysis

-   Calcd: C: 71.16, H: 7.39, N: 7.90, 0: 13.54-   Found: C: 71.20, H: 7.36, N: 7.80-   ¹H-NMR(CDCl₃): 1.13-1.19 (2H, m), 1.64-1.79 (5H, m), 2.09 (3H, s),    2.53 (1H, t), 2.72 (2H, t, J=9.7 Hz), 2.93-3.05 (5H, m), 3.23 (2H,    t, J=8.4 Hz), 3.80 (1H, d), 4.14 (2H, t, J=8.4 Hz), 5.61 (1H, d),    7.67 (1H, s), 7.72 (1H, s)

EXAMPLE 2

Synthesis of8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one

A mixture of 3.95 kg of8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-oneand 19.8 L of 2 N HCl was stirred at about 85° C. for about 10 hours.After cooled to about 35° C., 12 L of toluene was added to the reactionmixture, the layers were separated, and pH was adjusted to about 13 byadding 30% NaOH (about 10 L) to the aqueous layer while maintainingabout 30° C. Further, 20 L of a mixture of toluene-acetonitrile (1:1)was added thereto, and the layers were separated. To the aqueous layerwas added 12 L of a mixture of toluene-acetonitrile (1:1), and thelayers were separated. The organic layers were combined, 12 L of 30%brine was added thereto, and the layers were separated. To the organiclayer were added 346 g of active carbon and 346 g of silica gel,followed by stirring for about 15 minutes. The insolubles were filteredoff, and washed with 6 L of a mixture of toluene-acetonitrile (1:1). Thefiltrate was concentrated to a volume of the solution of about 7 L. Tothe residue was added 3 L of toluene, and the mixture was stirred atabout 40° C. Under nitrogen, 666 g of acetic acid was added at about 30°C. over about 15 minutes. The mixture was stirred at about 25° C. for1.5 hours and then at about 5° C. for 1 hour. Precipitated crystals wereseparated, and washed with 28 L of a mixture of toluene-acetonitrile(1:1) cooled to about 5° C. The wet crystals were suspended in 65 L of amixture of toluene-acetonitrile (1:1), 30% NaOH was added (about 10 L)thereto, pH was adjusted to 13.5, and the layers were separated. To theaqueous layer was added 8 L of a mixture of toluene-acetonitrile (1:1),and the layers were separated. The organic layers were combined, andwashed with 12 L of 30% brine. The organic layer was washed again with12 L of 30% brine. To the organic layer were added 346 g of activecarbon and 346 g of silica gel, the mixture was stirred for about 15minutes. The insolubles were filtered off, and washed with 6 L of amixture of toluene-acetonitrile (1:1). The same procedures were repeatedtwice. The organic layer was concentrated, and 5 L of water was added tothe residue, followed by re-concentration. The same procedures wererepeated twice. Under nitrogen, 5 L of water was added to the residue,and 5 L of 30% brine was added at about 20° C. over about 15 minutes.Seed crystals were added, and the mixture was stirred at about 20° C.for 1.5 hours and then at about 5° C. for 1 hour. The desired compoundwas separated under nitrogen, washed with 4 L of 30% brine cooled toabout 5° C., and dried to give 1.78 kg (yield 51%) of the desiredcompound as crystals.

Elementary Analysis

-   Calcd: C: 73.05, H: 7.74, N: 8.97, O: 10.24-   Found: C: 72.90, H: 7.65, N: 9.06-   ¹H-NMR(CDCl₃): 1.12-1.22 (2H, m), 1.40-1.50 (1H, m), 1.64-1.74 (4H,    m), 2.59 (2H, td, J=12, 2.4 Hz), 2.72 (2H, t, J=7.5 Hz), 2.93 (2H,    t, J=7.5 Hz), 3.00-3.10 (4H, m), 3.23 (2H, t, J=8.4 Hz), 4.13 (2H,    t, J=8.4 Hz), 7.67 (1H, s), 7.72 (1H, s)

EXAMPLE 3

Synthesis of8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one

A mixture of 600 g of8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,6 L of acetonitrile, 0.3 L of water, 345 g (1.3 equivalent) of potassiumcarbonate and 278 g (1 equivalent) of 3-fluorobenzyl chloride wasstirred at about 55° C. and 12 L of water was added dropwise theretoover about 20 minutes while maintaining about 45° C. The mixture wasstirred at about 55° C. for 1.5 hours, and at about 20° C. for 3 hours.Precipitated crystals were separated, and washed with 15 L of water. Thewet crystals were suspended in 8.0 L of 10% hydrous methanol-denaturedethanol. The material was dissolved at about 70° C., and passed througha dust-removing filter. The filtrate was stirred at about 20° C. for 1.5hours, 6.9 L of water was added thereto, and the mixture was stirred atabout 20° C. for 3 hours. Crystals were separated, washed with 1.8 L of50% hydrous methanol-denatured ethanol twice and dried to obtain 0.71 kg(yield 88%) of the desired compound as crystals.

-   m.p.: 114° C.

Elementary Analysis Calcd: C: 74.26, H: 6.95, N: 6.66, F: 4.52, O: 7.61Found: C: 74.27, H: 6.97, N: 6.53, F: 4.52 ¹H-NMR(DMSO-d₆): 1.16 (2H,qd, J=11.9, 3.5 Hz), 1.21-1.30 (1H, m), 1.53 (2H, m), 1.64-1.67 (2H, d,J=11.9 Hz), 1.89 (2H, t, J=11.9 Hz), 2.59 (2H, t, J=7.8 Hz), 2.77 (2H,d, J=11.9 Hz), 2.94 (2H, t, J=7.6 Hz), 2.97 (2H, J=7.8 Hz), 3.17 (2H, t,8.5 Hz), 3.44 (2H, s), 3.98 (2H, t, J=8.5 Hz), 7.05 (1H, m), 7.10 (1H,d), 7.12 (1H, d, J=7.9 Hz), 7.35 (1H, td, J=7.9, 6.1Hz), 7.72 (1H, m),7.73 (1H, m) IR(KBr, vcm⁻¹): 2020, 1660, 1597, 1491, 1387, 1336, 1128,802

-   UVmax(CH₃CN): 310 nm

EXAMPLE 4

Synthesis of8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one

A mixture of 1-acetyl-4-piperidinepropionic acid (1.99 g, 9.99 mmol),1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one (1.73 g, 9.99mmol) and polyphosphoric acid (24 g) was stirred at about 105° C. for 7hours under nitrogen. Cold water (16 mL) at about 5° C. was slowly addeddropwise thereto at −40 to 70° C. and 25% aqueous ammonia was addeddropwise thereto at 40 to 50° C. to adjust pH to 8.5. A mixture oftoluene-acetonitrile (1:1) (20 mL) was added. The layers were separated,a mixture of toluene-acetonitrile (1:1) (10 mL) was added to the aqueouslayer, and the layers were separated. The organic layers were combined,and concentrated to a volume of the solution of ⅕. Diisoporpyl ether (7mL) was added to the residue to precipitate crystals. The mixture wasstirred at about 25° C. for about 1 hour and then at 0 to 5° C. forabout 1 hour. Precipitated crystals were separated, washed withdiisopropyl ether (3 mL) and dried to obtain 3.47 g (yield 98.6%) of thedesired compound as crystals.

EXAMPLE 5

Synthesis of8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one

8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one(10 g, 28.2 mmol) and 2 N hydrochloric acid (50 mL) were stirred atabout 90° C. for 8 hours. After cooled to about 25° C., toluene (30 mL)was added to the reaction mixture, the layers were separated, and 30%aqueous sodium hydroxide solution (16 mL) was added to the aqueous layerto adjust pH to 13.8. A mixture of toluene-acetonitrile (1:1) (50 mL)was added thereto, and the layers were separated. A mixture oftoluene-acetonitrile (1:1) (50 mL) was added to aqueous layer, and thelayers were separated. The organic layers were combined, 30% brine (30mL) was added, and the layers were separated. The organic layer wasconcentrated under reduced pressure to obtain 8.55 g (yield 92.5%) ofthe desired compound as a solid.

EXAMPLE 6

Synthesis of8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one

A mixture of8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one(4 g, 12.8 mmol), acetonitrile (26 mL), water (1.4 mL), potassiumcarbonate (2.3 g, 16.6 mmol) and 3-fluorobenzyl chloride (1.55 mL, 12.8mmol) was stirred at about 50 to 55° C. After cooling, water (84 mL) wasadded dropwise thereto. The mixture was stirred at room temperature forabout 1 hour. Precipitated crystals were separated, washed with water(80 mL) and dried to obtain 5.09 g (yield 95%) of the desired compoundas crystals.

Industrial Applicability

According to the process of the present invention, a tricyclic fusedheterocyclic derivative having acetylcholinesterase inhibitory activitywhich is useful as a medicament, and an intermediate thereof can beprepared at a better yield, effectively and at an industrial large scaleby an inexpensive and simple process.

1. A process for producing a compound represented by the formula:

wherein the symbols are as defined hereinafter, or a salt thereof, whichcomprises: reacting a compound represented by the formula:

wherein one of the ring A and the ring B is a 5- to 9-membered aromaticor non-aromatic heterocyclic ring containing 1 to 3 hetero atom(s)selected from a nitrogen atom, an oxygen atom and a sulfur atom, whichmay be substituted with 1 to 5 substituent(s) selected from a halogenatom, a nitro group. a cyano group, an oxo group, a hydroxy group, aC₁₋₆ alkyl group, a C₁₋₄ alkoxy group, a C₁₋₄ alkylthio group, an aminogroup, a mono-or di-C₁₋₄ alkylamino group, a 5- to 7-membered cyclicamino group which may have 1 to 3 hetero atom(s) selected from anitrogen atom, an oxygen atom and a sulfur atom in addition to carbonatoms and one nitrogen atom, a C₁₋₄ alkyl-carbonylamino group, a C₁₋₄alkylsulfonylamino group, a C₁₋₄ alkoxy-carbonyl group, a carboxylgroup, a C₁₋₄ alkyl-carbonyl group, a carbamoyl group, a mono- ordi-C₁₋₄ alkyl-carbamoyl group, and a C₁₋₆ alkylsulfonyl group, and theother is a 5- to 8-membered aromatic or non-aromatic heterocyclic ringcontaining 1 to 3 atom(s) selected from a nitrogen atom, an oxygen atomand a sulfur atom or a 5- to 8-membered saturated or unsaturatedcarbocyclic ring, which may be substituted with 1 to 5 substituent(s)selected from a halogen atom, a nitro group, a cyano group, an oxogroup, a hydroxy group, a C₁₋₆ alkyl group, a C₁₋₄ alkoxy group, a C₁₋₄alkylthio group, an amino group, a mono-or di-C₁₋₄ alkylamino group, a5- to 7-membered cyclic amino group which may have 1 to 3 hetero atom(s)selected from a nitrogen atom, an oxygen atom and a sulfur atom inaddition to carbon atoms and one nitrogen atom, a C₁₋₄alkylcarbonylamino group, a C₁₋₄ alkylsulfonylamino group, a C₁₋₄alkoxy-carbonyl group, a carboxyl group, a C₁₋₆ alkyl-carbonyl group, acarbamoyl group, a mono- or di-C₁₋₄ alkyl-carbamoyl group, and a C₁₋₆alkylsulfonyl group, or a salt thereof, with a compound represented bythe formula:

wherein R is a hydrogen atom, an optionally substituted alkyl group oran optionally substituted acyl group, and n is an integer of 1 to 6, ora salt thereof, in the presence of a phosphorus compound.
 2. The processaccording to claim 1, wherein the phosphorus compound is apolyphosphoric acid.
 3. The process according to claim 1, wherein theformula:

wherein each of the ring A″ and the ring B″ ring is an optionallysubstituted nitrogen-containing heterocyclic ring.
 4. The processaccording to claim 1, wherein R is an optionally substituted acyl group.5. The process according to claim 1, wherein R is an acetyl group.
 6. Aprocess for producing8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,which comprises reacting1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with1-acetyl-4-piperidinepropionic acid in the presence of a phosphoruscompound.
 7. A process for producing a compound represented by theformula:

wherein the symbols are as defined hereinafter, or a salt thereof, whichcomprises: reacting a compound represented by the formula:

wherein one of the ring A and the ring B is a 5- to 9-membered aromaticor non-aromatic heterocyclic ring containing 1 to 3 hetero atom(s)selected from a nitrogen atom, an oxygen atom and a sulfur atom, whichmay be substituted with 1 to 5 substituent(s) selected from a halogenatom, a nitro group, a cyano group, an oxo group, a hydroxy group, aC₁₋₆ alkyl group, a C₁₋₄ alkoxy group, a C₁₋₄ alkylthio group, an aminogroup, a mono- or di-C₁₋₄ alkylamino group, a 5- to 7-membered cyclicamino group which may have 1 to 3 hetero atom(s) selected from anitrogen atom, an oxygen atom and a sulfur atom in addition to carbonatoms and one nitrogen atom, a C₁₋₄ alkyl-carbonylamino group, a C₁₋₄alkylsulfonylamino group, a C₁₋₄ alkoxy-carbonyl group, a carboxylgroup, a C₁₋₆ alkyl-carbonyl group, a carbamoyl group, a mono- ordi-C₁₋₄ alkyl-carbamoyl group, and a C₁₋₆ alkylsulfonyl group, and theother is a 5- to 8-membered aromatic or non-aromatic heterocyclic ringcontaining 1 to 3 atom(s) selected from a nitrogen atom, an oxygen atomand a sulfur atom or a 5- to 8-membered saturated or unsaturatedcarbocyclic ring, which may be substituted with 1 to 5 substituent(s)selected from a halogen atom, a nitro group, a cyano group, an oxogroup, a hydroxy group, a C₁₋₆ alkyl group, a C₁₋₄ alkoxy group, a C₁₋₄alkylthio group, an amino group, a mono-or di-C₁₋₄ alkylamino group, a5- to 7-membered cyclic amino group which may have 1 to 3 hetero atom(s)selected from a nitrogen atom, an oxygen atom and a sulfur atom inaddition to carbon atoms and one nitrogen atom, a C₁₋₄alkylcarbonylamino group, a C₁₋₄ alkylsulfonylamino group, a C₁₋₆alkoxy-carbonyl group, a carboxyl group, a C₁₋₄ alkyl-carbonyl group, acarbamoyl group, a mono- or di-C₁₋₄ alkyl-carbamoyl group, and a C₁₋₆alkylsulfonyl group, or a salt thereof, with a compound represented bythe formula:

wherein R′ is an optionally substituted acyl group, and n is an integerof 1 to 6, in the presence of a phosphorus compound, and deacylating theresulting compound represented by the formula:

wherein the symbols are as defined above, or a salt thereof.
 8. Theprocess according to claim 7, wherein deacylation is conducted withabout 1 to about 6 N hydrochloric acid.
 9. A process for producing8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one, which comprises reacting1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with1-acetyl-4-piperidinepropionic acid in the presence of a phosphoruscompound, and deacetylating the resulting8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one.
 10. A process for producing a compoundrepresented by the formula:

wherein the symbols are as defined hereinafter, or a salt thereof, whichcomprises: reacting a compound represented by the formula:

wherein one of the ring A ring and the ring B is a 5- to 9-memberedaromatic or non-aromatic heterocyclic ring containing 1 to 3 heteroatom(s) selected from a nitrogen atom, an oxygen atom and a sulfur atom,which may be substituted with 1 to 5 substituent(s) selected from ahalogen atom, a nitro group, a cyano group, an oxo group, a hydroxygroup, a C₁₋₆ alkyl group, a C₁₋₄ alkoxy group, a C₁₋₄ alkylthio group,an amino group, a mono-or di-C₁₋₄ alkylamino group, a 5- to 7-memberedcyclic amino group which may have 1 to 3 hetero atom(s) selected from anitrogen atom, an oxygen atom and a sulfur atom in addition to carbonatoms and one nitrogen atom, a C₁₋₄ alkyl-carbonylamino group, a C₁₋₄alkylsulfonylamino group, a C₁₋₄ alkoxy-carbonyl group, a carboxylgroup, a C₁₋₆ alkyl-carbonyl group, a carbamoyl group, a mono- ordi-C₁₋₄ alkyl-carbamoyl group, and a C₁₋₆ alkylsulfonyl group, and theother is a 5- to 8-membered aromatic or non-aromatic heterocyclic ringcontaining 1 to 3 atom(s) selected from a nitrogen atom, an oxygen atomand a sulfur atom or a 5- to 8-membered saturated or unsaturatedcarbocyclic ring, which may be substituted with 1 to 5 substituent(s)selected from a halogen atom, a nitro group, a cyano group, an oxogroup, a hydroxy group, a C₁₋₆ alkyl group, a C₁₋₄ alkoxy group, a C₁₋₄alkylthio group, an amino group, a mono-or di-C₁₋₄ alkylamino group. a5- to 7-membered cyclic amino group which may have 1 to 3 hetero atom(s)selected from a nitrogen atom, an oxygen atom and a sulfur atom inaddition to carbon atoms and one nitrogen atom, a C₁₋₄alkylcarbonylamino group, a C₁₋₄ alkylsulfonylamino group, a C₁₋₄alkoxy-carbonyl group, a carboxyl group, a C₁₋₆ alkyl-carbonyl group, acarbamoyl group, a mono- or di-C₁₋₄ alkyl-carbamoyl group, and a C₁₋₆alkylsulfonyl group, or a salt thereof, with a compound represented bythe formula:

wherein R′ is an optionally substituted acyl group, and n is an integerof 1 to 6, or a salt thereof, in the presence of a phosphorus compound,deacylating the resulting compound represented by the formula:

wherein the symbols are as defined, or a salt thereof, and reacting theresulting compound represented by the formula:

wherein the symbols are as defined above, or a salt thereof, with acompound represented by the formula:

wherein the ring C is an optionally substituted benzene ring, and W is aleaving group, or a salt thereof.
 11. The process according to claim 10,wherein the ring C is a benzene ring substituted with a halogen.
 12. Aprocess for producing8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one, which comprises reacting1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with1-acetyl-4-piperidinepropionic acid in the presence of a phosphoruscompound, deacetylating the resulting8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one, and reacting the resulting8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with 3-fluorobenzyl chloride.